TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

Daniel Bronder, Anthony Tighe, Darawalee Wangsa, Dali Zong, Thomas J. Meyer, Rene Wardenaar, Paul Minshall, Daniela Hirsch, Kerstin Heselmeyer-Haddad, Louisa Nelson, Diana Spierings, Joanne Mcgrail, Maggie Cam, André Nussenzweig, Floris Foijer, Thomas Riedel, Stephen Taylor

Research output: Contribution to journalArticlepeer-review


High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). However, direct causes of CIN, such as mutations in DNA replication and mitosis genes, are rare in HGSOC. We therefore asked whether oncogenic mutations that are common in HGSOC can indirectly drive CIN in non-transformed human fallopian tube epithelial cells. To model homologous recombination deficient HGSOC, we sequentially mutated TP53 and BRCA1 then overexpressed MYC. Loss of p53 function alone was sufficient to drive the emergence of subclonal karyotype alterations. TP53 mutation also led to global gene expression changes, influencing modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function. Both transcriptional deregulation and karyotype diversity were exacerbated by loss of BRCA1 function, with whole-genome doubling events observed in independent p53/BRCA1-deficient lineages. Thus, our observations indicate that loss of the key tumour suppressor TP53 is sufficient to deregulate multiple cell cycle control networks and thereby initiate CIN in pre-malignant fallopian tube epithelial cells. This article has an associated First Person interview with the first author of the paper.

Original languageEnglish
Article numberdmm049001
JournalDMM Disease Models and Mechanisms
Issue number11
Publication statusPublished - 1 Nov 2021


  • BRCA1
  • Chromosomal instability
  • Fallopian tube
  • High-grade serous ovarian cancer
  • MYC
  • TP53
  • Epithelial Cells/metabolism
  • Fallopian Tubes/metabolism
  • Mutation/genetics
  • Humans
  • Tumor Suppressor Protein p53/genetics
  • Female
  • Cystadenocarcinoma, Serous/genetics
  • Chromosomal Instability
  • Ovarian Neoplasms/pathology

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


Dive into the research topics of 'TP53 loss initiates chromosomal instability in fallopian tube epithelial cells'. Together they form a unique fingerprint.

Cite this